5-hydroxytryptamine, a neurotransmitter that carries signal in the brain and nerves, plays a very important role in central nervous system (CNS) dysfunction, especially in anxiety disorder, depression, aggression and impulsivity. Regulation of the central nervous system dysfunction is possible either by antagonistic or agonistic action on a certain type of 5-hydroxytryptamine receptors. By now, at least 14 different 5-hydroxytryptamine receptors have been identified. These receptors can be divided into distinct families, independently recorded as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 with the subtypes in each family denoted by letters such as a, b and c. The 5-HT1A receptor is a G-protein-coupled receptor widely distributed in regions that receives serotonergic input from the raphe nuclei: the frontal cortex, septum, amygdala, hippocampus, and hypothalamus. In these cortico-limbic regions, 5-HT1A is distributed post-synaptically. At the same time, the 5-HT1A receptor also serves as the autoreceptor of presynaptic membrane on the raphe nuclei, reducing the discharge rate of neurons (i.e., the amount of 5-hydroxytryptamine released per action potential), and the synthesis of the neurotransmitter, and reducing the serotonergic activity of its projection areas. Activation of the presynaptic 5-HT1A receptor may also indirectly reduce serotonergic transmission through the inhibition of tyrosine hydroxylase synthesis, as well as the activity of glutamatergic pathway that originates in the medial prefrontal cortex and projects to the raphe nuclei (Jonathan Savitz, Irwin Lucki, Wayne C. Drevets. 5-HT1A receptor function in major depressive disorder. Prog Neurobiol. 2009, 88(1): 17-31).
Depression is the most important of all therapeutic indications related to 5-hydroxytryptamine disorder since it is the fourth leading burdensome disease in the world according to the World Health Organization. By 2020, depression is projected to rank second in all disability-adjusted life years. (Bromet E, Andrade L H, Hwang I, et al., Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011, 9: 90).
Historically, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) revolutionized the pharmacologic treatment of a mood disorder in the 1950s, mostly by blocking neurotransmitter (dopamine, norepinephrine, and 5-hydroxytryptamine). However, the non-selective and undesired side effects limited their use. In 1980s, the discovery of selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) changed the landscape. As a class, the SSRIs boast similar efficacy compared to the TCAs, and an improved AE profile with less tendency for toxicity in overdose (Sarko J. Andidepressant, old and new. A review of their adverse effects and toxicity in overdose. Emerg Med Clin North Am, 2000; 18 (4): 637-54, incorporated herein by reference).
Conventional SSRIs therapeutically increase available 5-hydroxytryptamine by inhibiting its reuptake and modulating its transmission. However, after using of SSRIs, administration of SSRIs also stimulates pre-synaptic 5-HT1A autoreceptors, which decreases the release of 5-hydroxytryptamine and subsequently reduces 5-hydroxytryptamine concentrations in the synapse. However, after chronic administration, the stimulation of the 5-HT1A autoreceptors is overcome via desensitization and the SSRIs are able to exert normal regulating effect. It is postulated that this stimulation of the autoreceptor is the causative factor in the delayed therapeutic effect of the SSRIs (Celada P, Puig M, Amargos-Bosch M, et al. The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci, 2004, 29(4): 252-65). Thus, overcoming the negative feedback effect of 5-HT1A autoreceptors antagonists held the promise of increasing and accelerating clinical antidepressant effects.
Compared to SSRIs, 5-HT1A receptor agonists or partial agonists act directly on postsynaptic 5-hydroxytryptamine receptors to increase 5-hydroxytryptamine neurotransmission during the SSRI latency effect period. Feiger and Wilcox demonstrated that the buspirone and gepirone were clinically effective 5-HT1A partial agonists (Feiger, A. Psychopharmacol. Bull. 1996, 32: 659-65, incorporated herein by reference). The addition of buspirone to standard SSRI treatment produced a marked improvement in patients previously unresponsive to standard treatment for depression (Dimitriou, E. J. Clin. Psychopharmacol., 1998, 18: 465-9).